Synthesis of the first diethylenetriaminepentahydroxamic acid (DTPH) bifunctional chelating agent.
Synthesis of the first diethylenetriaminepentahydroxamic acid (DTPH) bifunctional chelating agent.
复制标题
第一个二乙烯三胺五异羟肟酸（DTPH）双功能螯合剂的合成。
DOI：
10.1021/bc010092x
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发表时间：
2002
影响因子：
4.7
通讯作者：
Buchsbaum,DonaldJ
中科院分区：
文献类型：
--
作者：
Safavy,Ahmad;SmithJr,DaleC;Bazooband,Alireza;Buchsbaum,DonaldJ
报道了以二乙烯三胺五乙酸（DTPA）氨基氮杂烷基为核心，合成了新型五羟肟酸双功能螯合剂（BCA）。本文描述了DTPA结构的合理修饰，这可能导致其螯合性能的增强，增加了由该螯合剂结合的诊断和治疗金属的收集，并可能显著改善该化合物的体内行为。进一步改善DTPA配体-金属配合物的稳定性可能会改善诊断和治疗结果，如肿瘤与正常组织的比率和靶传递放射性。将羟基酸酯功能与DTPA的氮杂烷基骨架结合可能是产生这种高稳定性的合适方法。众所周知，羟基酸盐对不同过渡金属的亲和力和DTPA作为多功能螯合剂的有利性质证明了这一理论的合理性。以此为基础，设计并合成了Nα，Nα,Nε，Nε-五akis[[（n -羟基- n -甲基]羰基）甲基]- 2,6 -二氨基-4-扎己酸肼（5，DTPH），总收率为40.7%。将该化合物与单克隆抗体（MAb） ΔCh2HuCC49偶联，作为模型蛋白，以评估该分子作为BCA的效率。报道了DTPH−ΔCh2HuCC49与luteium -177 （177Lu）结合物的放射标记和标记的结合物在携带LS174T人结肠癌异种移植物的胸腺裸鼠中的生物分布。
Synthesis of a new pentahydroxamic acid bifunctional chelating agent (BCA), constructed on the aminoazaalkyl core of diethylenetriaminepentaacetic acid (DTPA), is reported. Rational modifications in the structure of DTPA, which could result in an enhancement of its chelation properties, add to the collection of diagnostic and therapeutic metals bound by this chelator, and might implement significant improvements in the in vivo behavior of this compound, are described. Further improvements in the stability of the ligand−metal complexes of DTPA may improve both diagnostic and therapeutic outcomes such as tumor-to-normal tissue ratios and target-delivered radioactivity. A combination of hydroxamate functions with the azaalkyl backbone of DTPA might be a suitable approach to generate such higher stabilities. This rationale may be justified by the well-known affinity of hydroxamates against different transition metals and favorable properties of DTPA as a versatile chelator. Thus, theN4,Nα,Nα,Nε,Nε-pentakis[[((N-hydroxy-N-methyl]carbonyl)methyl]-2, 6-diamino-4-azahexanoic hydrazide (5, DTPH) was designed and synthesized through a convergent synthesis and in 40.7% overall yield. Conjugation of this compound to the monoclonal antibody (MAb) ΔCh2HuCC49, used as a model protein, was carried out to evaluate the efficiency of this molecule as a BCA. Radiolabeling of the DTPH−ΔCh2HuCC49 conjugate with lutetium-177 (177Lu) and biodistribution of the labeled conjugate in athymic nude mice, bearing LS174T human colon carcinoma xenografts, are reported.